Studies on the mechanism of dimethylnitrosamine-induced acute liver injury in mice.
Male and female adult C3H- +/+, C3H-gld/gld.lpr/lpr (gld.lpr) and CBA-lprcg/lprcg (lprcg) mice were given a single i.p. dose of 30 mg/kg dimethylnitrosamine (DMN). Liver tissues were collected from mice killed 6, 12, 24 and 36 hrs post treatment, and the progression of the lesions was characterized morphologically and by the TUNEL method. DMN induced centrilobular hepatic injury accompanied with acute hemorrhage, and all mice died 36 to 48 hrs after the dosing. At 12 hrs after DMN administration, centrilobular hepatocytes revealed nuclear chromatin clumping. At 24 hrs, hepatocyte nuclei became fragmented to form apoptotic cells. Ultrastructurally, chromatin was condensed into a compact granular mass or crescent granular cap at the nuclear periphery. At 36 hrs, the number of apoptotic cells increased and they protruded into the sinusoid or were engulfed by the neighboring hepatocytes. A TUNEL-positive signal preceded the morphological changes and a few normal appearing centrilobular hepatocytes were positive 6 hrs post dosing. Endothelial damage was seen immunohistochemically at 24 hrs by disruption of type IV collagen and factor VIII-related antigen, resulting in massive hemorrhage in the centrilobular to mid zone. No inflammatory reactions were observed throughout the degeneration. The findings indicate that a single i.p. administration of DMN induced severe and fatal toxicity in liver tissues in mice which resembled human fulminant hepatitis. However, as gld-lpr and lprcg mice defective in apoptosis through the Fas system also showed similar severe liver damage, the Fas/Fas ligand system is not involved in DMN-induced liver apoptosis. No other organs or tissues were damaged, and the control mouse liver was intact.
Oyaizu
T
T
Department of Pathology, Kansai Medical University, Osaka, Japan.
Shikata
N
N
Senzaki
H
H
Matsuzawa
A
A
Tsubura
A
A
D000208:Acute Disease; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D004128:Dimethylnitrosamine / Q000633:toxicity*; D005260:Female; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects* / Q000473:pathology* / Q000648:ultrastructure; D008107:Liver Diseases / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D018345:Mice, Knockout
D004128:Dimethylnitrosamine